AlphaFold and the amyloid landscape

Pinheiro, Francisca; Santos, Jaime; Ventura, Salvador

doi:10.1016/j.jmb.2021.167059

Cited by 58 publications

(52 citation statements)

References 157 publications

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“…Furthermore, many amyloid-forming proteins, such as alpha-synuclein, amylin, and the αβ42 peptide, also fall into Cluster 3. This result corroborates previous observations that AlphaFold2’s approach is not yet sensitive enough to robustly predict the conformations of fibril-forming proteins 29; 30 .…”

Section: Resultssupporting

confidence: 91%

AlphaFold2 fails to predict protein fold switching

Chakravarty

Porter

2022

Preprint

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AlphaFold2 has revolutionized protein structure prediction by leveraging sequence information to rapidly model protein folds with atomic-level accuracy. Nevertheless, previous work has shown that these predictions tend to be inaccurate for structurally heterogeneous proteins. To systematically assess factors that contribute to this inaccuracy, we tested AlphaFold2's performance on 98 fold-switching proteins, which assume at least two distinct-yet-stable secondary and tertiary structures. Topological similarities were quantified between five predicted and two experimentally determined structures of each fold-switching protein. Overall, 94% of AlphaFold2 predictions captured one experimentally determined conformation but not the other. Despite these biased results, AlphaFold2's estimated confidences were moderate-to-high for 74% of fold-switching residues, a result that contrasts with overall low confidences for intrinsically disordered proteins, which are also structurally heterogeneous. To investigate factors contributing to this disparity, we quantified sequence variation within the multiple sequence alignments used to generate AlphaFold2's predictions of fold-switching and intrinsically disordered proteins. Unlike intrinsically disordered regions, whose sequence alignments show low conservation, fold-switching regions had conservation rates statistically similar to canonical single-fold proteins. Furthermore, intrinsically disordered regions had systematically lower prediction confidences than either fold-switching or single-fold proteins, regardless of sequence conservation. These results suggest that AlphaFold2's high prediction confidences for fold switchers stem from the assumption that proteins assume one dominant fold. Our results emphasize the need to look at protein structure as an ensemble and suggest that systematic examination of fold-switching sequences may reveal propensities for multiple stable secondary and tertiary structures.

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Section: Resultssupporting

confidence: 91%

AlphaFold2 fails to predict protein fold switching

Chakravarty

Porter

2022

Preprint

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“…Using the recently published program AlphaFold 2 [ 41 ], we predicted 3D models for monomers, trimers, and tetramers of the R23F, R23DI, and R23EI peptides ( Figure 3 ). Despite the significant success of AlphaFold 2 in predicting the tertiary structure of proteins, its use for modeling the structure of multi-domain proteins (such as ribosomal S1 protein from S. aureus ), intrinsically disordered regions, and amyloidogenic peptides has restrictions [ 51 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple Antimicrobial Effects of Hybrid Peptides Synthesized Based on the Sequence of Ribosomal S1 Protein from Staphylococcus aureus

Кравченко

Domnin

Grishin

et al. 2022

IJMS

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The need to develop new antimicrobial peptides is due to the high resistance of pathogenic bacteria to traditional antibiotics now and in the future. The creation of synthetic peptide constructs is a common and successful approach to the development of new antimicrobial peptides. In this work, we use a simple, flexible, and scalable technique to create hybrid antimicrobial peptides containing amyloidogenic regions of the ribosomal S1 protein from Staphylococcus aureus. While the cell-penetrating peptide allows the peptide to enter the bacterial cell, the amyloidogenic site provides an antimicrobial effect by coaggregating with functional bacterial proteins. We have demonstrated the antimicrobial effects of the R23F, R23DI, and R23EI hybrid peptides against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa, Escherichia coli, and Bacillus cereus. R23F, R23DI, and R23EI can be used as antimicrobial peptides against Gram-positive and Gram-negative bacteria resistant to traditional antibiotics.

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“…However, the attempt to model the conformation of amyloidogenic fragments using AlphaFold2 leads to structures that differ from those based on molecular dynamics or experimental NMR restraints. In the predicted models, a higher proportion of the full-length parent protein is retained possibly because of the use of co-evolutionary methods in AlphaFold2 that may represent a major limitation in predicting the structure of protein aggregation intermediates ( Pinheiro et al, 2021 ). Many proteins can be transformed into amyloid fibrils in vitro , but only a few make deposits in vivo causing amyloid disease ( Chiti and Dobson, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

Faravelli

Mondani

Mangione

et al. 2022

Front. Mol. Biosci.

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The globular to fibrillar transition of proteins represents a key pathogenic event in the development of amyloid diseases. Although systemic amyloidoses share the common characteristic of amyloid deposition in the extracellular matrix, they are clinically heterogeneous as the affected organs may vary. The observation that precursors of amyloid fibrils derived from circulating globular plasma proteins led to huge efforts in trying to elucidate the structural events determining the protein metamorphosis from their globular to fibrillar state. Whereas the process of metamorphosis has inspired poets and writers from Ovid to Kafka, protein metamorphism is a more recent concept. It is an ideal metaphor in biochemistry for studying the protein folding paradigm and investigating determinants of folding dynamics. Although we have learned how to transform both normal and pathogenic globular proteins into fibrillar polymers in vitro, the events occurring in vivo, are far more complex and yet to be explained. A major gap still exists between in vivo and in vitro models of fibrillogenesis as the biological complexity of the disease in living organisms cannot be reproduced at the same extent in the test tube. Reviewing the major scientific attempts to monitor the amyloidogenic metamorphosis of globular proteins in systems of increasing complexity, from cell culture to human tissues, may help to bridge the gap between the experimental models and the actual pathological events in patients.

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AlphaFold and the amyloid landscape

Cited by 58 publications

References 157 publications

AlphaFold2 fails to predict protein fold switching

AlphaFold2 fails to predict protein fold switching

Multiple Antimicrobial Effects of Hybrid Peptides Synthesized Based on the Sequence of Ribosomal S1 Protein from Staphylococcus aureus

Amyloid Formation by Globular Proteins: The Need to Narrow the Gap Between in Vitro and in Vivo Mechanisms

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